The medical, social and legal problems caused by alcohol abuse and alcoholism are among the major public health problems in North America today. Tolerance is believed to play an important role in increasing alcohol (EtOH) consumption and dependence. Development of new measures to prevent or reverse tolerance and dependence will be helped by a better understanding of how EtOH acts on brain cells, and how they become tolerant (resistant) to these actions. The speed with which EtOH decreases the excitability of the neuronal membrane suggests that it acts by changing the functional state of one or more receptor-activated ion conductance channels in the cell membrane. In current research, we have found that the GABAA-receptor/chloride-channel complex, on which the benzo-diazepines and barbiturates act, is not a primary site of EtOH action or of tolerance development, despite the occurrence of behavioral cross-tolerance between EtOH and these drugs. However, recent work shows that EtOH is a potent inhibitor of the opening of a specific calcium/sodium ion channel by the binding of glutamate to the NMDA receptor. Tolerance is a complex process, sharing many features with learning and memory, and the NMDA receptor is known to play a fundamental role in cellular processes underlying learning. We have found that NMDA receptor blockers prevent the development of tolerance to.EtOH and cross-tolerance between it and pentobarbital or diazepam. In contrast, we have found that vasopressin (AVP) increases the acute effects of EtOH (both behavioral and biochemical), facilitates tolerance development, and maintains tolerance after EtOH intake has ceased. These actions of AVP depend upon intact serotonin (5-HT) fibers from the median raphe nucleus to the medial septum in the brain. We propose to analyze these processes by: (1) identifying the sites of interconnection between AVP, 5-HT and NMDA neurons in the septum; (2) examining the effects of specific NMDA enhancers and NMDA lesions in the septum on development of tolerance; (3) characterizing fully the behavioral features and extent of tolerance and cross-tolerance produced by AVP given in combination with EtOH; (4) assessing the ability of AVP to enhance the effects of other drugs (e.g., opiates, cannabis, cocaine); and (5) comparing the effects of AVP on behavioral tolerance and on the cos regulatory system through which AVP (and possibly NMDA and 5-HT) receptors are thought to produce cellular adaptive changes, including tolerance and learning.